Taxoids are a class of derivatives from taxol. These are antitumor agents which have been shown to be active against leukemia, colon cancer, breast cancer, melanoma, sarcomas, and lewis lung tumor systems. Taxoids are poorly water soluble and pose formulation related problems to prepare safe and stable pharmaceutical composition.
The commercially available I.V. taxoids formulation marketed by Bristol-Myers Squibb (Taxol®) comprises 6 mg/ml of paclitaxel dissolved in a mixture of 50:50 of Cremophor EL (polyoxyethylated castor oil) and dehydrated ethanol. The said composition has shown a loss of potency of greater than 60% after storage at 50° C. for 12 weeks which was attributed to the decomposition of paclitaxel during storage. In general, the amount of Cremophor EL necessary to deliver the required dose of paclitaxel is significantly higher than that administered with other drugs currently formulated in Cremophor EL. The use of Cremophor EL has been attributed to several toxic effects such as vasodilation, dyspnea and hypotension. Both poor oral absorption of paclitaxel molecule and parenteral toxicity of paclitaxel injection suggest the need of a high bio-available oral formulation of the same.
Tarr et al. (1987) Pharm. Res. 4:162-165, attempted to formulate taxol with Intralipid (trademark of RabiVitrum (formerly Cutter Medical)) and discloses the composition comprising soybean oil, lecithin, egg yolk phospholipids and glycerol. The poor solubility of taxol in soybean oil (0.3 mg/ml) made this vehicle unsuitable.
EP1480636 discloses a self emulsifying drug delivery system (SEEDS) of paclitaxel comprising vitamin E and a co-solvent selected from propylene glycol and ethanol, one or more bile salts like deoxycholic acid sodium salt (DOC-Na), tocopheryl polyethylene glycol 1000 succinate (TPGS) and tyloxapol. The composition according to the invention is suitable for intravascular or oral administration. The said patent further discloses that the physical stability of paclitaxel in microemulsion decrease with increasing concentration of paclitaxel in SEDDS composition. The animal pharmacokinetic study revealed that after intravenous administration of said formulation the AUC0-α of paclitaxel was 4392.1 ng·hr/ml at the dose of 2 mg/kg and increased to 10129.9 and 72846.3 ng·hr/ml at the dose of 5 mg/kg and 10 mg/kg, respectively. Further, for oral administration, the SEDDS were diluted with water (in 1:10) and the values of Cmax were found between 40 to 60 ng/ml at the doses of 2 to 10 mg/kg. The said formulation was co-administered with cyclosporine A at dose of 40 mg/kg body weight that resulted in a Cmax of 85 ng/ml and 1.59 fold increase in bioavailability against SEEDS alone. The highest bioavailability of paclitaxel in oral administration was achieved at the dose of 5 mg/kg with 1.25% w/w concentration of paclitaxel. Said patent concluded that there is a decrease in AUC with increase in dose as well as paclitaxel concentration in formulation due to saturable process in the absorption of oral paclitaxel.
U.S. Pat. No. 6,046,230 discloses use of admixture of polyethoxylated sorbitol oleic polyester and polyethylene glycol mono fatty acid ester for preparation of improved paclitaxel injection and polyethylene glycol and polyvinyl pyrrolidone to achieve the quick dispersion of paclitaxel and stability of the formulation up to 5 days. The concentration of paclitaxel in stock solution was 0.6% and when stock solution was diluted at the ratio of 1:10 and 1:50 in 0.9% NaCl, the precipitation of paclitaxel occurred after 72 hours.
US20040092428A1 discloses ethanol and cremophor free oral formulation comprising of paclitaxel (83 to 100 mg/ml), and one or more of oil (triacetin), solvent (PEG 400, transcutol), surfactant (polysorbate 80) and organic acid (citric acid). An inhibitor of P-glycoprotein (cyclosporine A) is also administered before, during, or after the administration of paclitaxel formulation in order to improve the uptake of paclitaxel by gastrointestinal system. The said formulation resulted in maximum plasma concentration of 0.35 μg/ml.
US 20050191323 discloses preparation of stable cremophor-free formulation comprising paclitaxel (6 mg/ml), one or more solubilizer selected from PEG-Vitamin E, quaternary ammonium salts, PEG monoacid fatty esters, PEG-glyceryl fatty esters, polysorbates, PEG-fatty alcohols. Paclitaxel formulation disclosed by present application contains stabilizer like citric acid to prevent the decomposition of paclitaxel and maintain the pH of composition. The paclitaxel concentration in composition was 1.2 mg/ml and stayed dissolved only for 48 hours. Animal pK study revealed that bioavailability of the formulation is lower than the commercially available formulation.
US20060292186A1 discloses oral anhydrous self-nanoemulsifying oily formulation (SNEOF) comprising paclitaxel (1.5 to 3.0% w/w), vitamin E, co-solvent selected from propylene glycol and ethanol or mixture thereof and surfactant selected from tyloxapol and TPGS or mixture thereof and optionally a bioenhancer (cyclosporine A). However, there was no significant improvement in bioavailability of the same formulation when administered in wild type mice.
Most of the above reports make use of cyclosporine A which is an immunosuppressive agent and hence is undesirable in the formulation.
Oral pharmaceutical compositions of paclitaxel with lower/poor bioavailability are associated with diarrhea.
Despite several attempts by many researchers, there is an unmet need to develop a pharmaceutical composition of taxoids which provides therapeutic level of taxoids in serum and said composition also improves the stability, solubility and bioavailability of taxoids.
The term “therapeutic level of taxoid in serum’ as used herein is referred to minimum effective concentration of taxoid in serum. As per the present invention “therapeutic level of taxoid in serum” should be at least 85.3 ng/ml (shicheng yang et al. pharmaceutical research 21(2), 2004).
The term “stable” as used herein is related to physical and/or chemical stability. In physical stability, the drug should not be crystallized or precipitated in the pharmaceutical composition during shelf life or stability conditions for at least three months. In chemical stability as per the international conference on harmonization (ICH) guidelines the active pharmaceutical ingredient should retain its 90% activity during the accelerated stability study for 3 months.